This application for a Specialized Program of Research Excellence in Pancreatic Cancer focuses on translational studies that address basic and clinical issues of importance to improving the outcome of patients with pancreatic cancer. Specifically, the research projects in this program seek to: 1) develop and test novel therapeutic strategies including chemotherapy, and chemoradiation therapy for patients with early and advanced pancreatic cancer; 2) undertake basic research studies in conjunction with clinical trials that will provide insight at the molecular level into the reasons for success and failure of the different strategies. The first project investigates potential of novel inhibitors of CDKS to block tumor progression and nociceptive signaling (pain) in preclinical animal models and in a phase I clinical trial in patients that have failed other therapies. The second project investigate further the molecular nature of radioresistance in patients with borderline resectable disease and proposes a clinical trial with inhibitors of the cholesterol synthesis pathway (Zometa) as a therapeutic intervention. The third project investigates therapeutic strategies that may be effective in SMAD4 mutant and SMAD4 wildtype tumors and proposes a novel clinical trial with a combination of an HDAC inhibitor (Belinostat) and an inhibitor to surviving (YM155) in patients that have failed other therapies. The fourth project investigates the possibility that a hypoxic an desmoplastic environment in pancreatic cancer affects metabolic features of the tumor and stroma that result in high endogenous production of cytidine, which in turn causes drug resistance to fluropyrimidines. Two therapeutic strategies that inhibit hypoxia (digoxin) and pyrimidine biosynthesis (leflunomide) will be investigated in a clinical trial, and the possibility that cytidine and associated metabolites can serve as biomarkers of drug resistance will be investigated. Our tissue core proposes to continue its unique collection of metastatic tumor samples through our rapid autopsy program, in addition to capturing samples associated with surgical resections. All projects are supported by administrative and biostatistics cores.